Scavenging of heme from plasma

Free heme is damaging to tissues as it intercalates into biologic membranes, perturbing lipid bilayers and promoting the conversion of low-density lipoprotein to cytotoxic oxidized products. Moreover, it represents a source of redox-active iron that, participating in the Fenton reaction, generates oxygen radicals (reviewed in Gutteridge 1989). Free heme in plasma is mainly generated from hemoglobin released by circulating erythrocytes in pathologic conditions associated with intravascular hemolysis. Free hemoglobin in plasma is scavenged by the extracellular protein haptoglobin. Haptoglobin is produced by the liver and secreted into the plasma. Haptoglobin binds dimers of hemoglobin subunits rather than the intact tetramer (reviewed in Nielsen et al. 2010, Levy et al. 2010, Ascenzi et al. 2005, Madsen et al. 2001). The resulting haptoglobin:hemoglobin complex is then bound by CD163, expressed on plasma membranes of monocytes and macrophages, and endocytosed. When the buffering capacity of plasma haptoglobin is overwhelmed, heme is released from methemoglobin and it is bound by albumin and then transferred to hemopexin (reviewed in Chiabrando et al. 2011, Nielsen et al. 2010, Tolosano et al. 2010, Ascenzi et al. 2005, Tolosano and Altruda 2002). Hemopexin is produced mainly in the liver. Once secreted into the plasma, hemopexin binds heme and the hemopexin:heme complex is then preferentially delivered to liver hepatocytes, bound by LRP1 (CD91) and endocytosed.

游离的血红素对组织具有损害作用，因其可嵌入生物膜中，干扰脂质双层并促进低密度脂蛋白转化为细胞毒性氧化产物。此外，它还代表了一种具有氧化还原活性的铁来源，参与芬顿反应，生成氧自由基（详见Gutteridge，1989年综述）。在病理条件下，与血管内溶血相关的循环红细胞释放的血红蛋白是血浆中游离血红素的主要来源。血浆中的游离血红蛋白被细胞外蛋白触珠蛋白清除。触珠蛋白由肝脏产生并分泌至血浆中。触珠蛋白与血红蛋白亚基的二聚体而非完整的四聚体结合（详见Nielsen等人，2010年；Levy等人，2010年；Ascenzi等人，2005年；Madsen等人，2001年综述）。由此形成的触珠蛋白：血红蛋白复合物随后被CD163结合，CD163表达于单核细胞和巨噬细胞的血浆膜上，并被内吞。当血浆中触珠蛋白的缓冲能力达到极限时，血红素从高铁血红蛋白中释放出来，并被白蛋白结合，随后转移至血红素结合蛋白（详见Chiabrando等人，2011年；Nielsen等人，2010年；Tolosano等人，2010年；Ascenzi等人，2005年；Tolosano和Altruda，2002年综述）。血红素结合蛋白主要由肝脏产生。一旦分泌到血浆中，血红素结合蛋白便与血红素结合，而血红素结合蛋白：血红素复合物随后优先被肝脏肝细胞上的LRP1（CD91）结合并被内吞。